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- PDB-5op8: Factor Inhibiting HIF (FIH) in complex with zinc and Molidustat -

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Basic information

Entry
Database: PDB / ID: 5op8
TitleFactor Inhibiting HIF (FIH) in complex with zinc and Molidustat
ComponentsHypoxia-inducible factor 1-alpha inhibitor
KeywordsOXIDOREDUCTASE / ON-HEME / DIOXYGENASE / OXYGENASE / DNA-BINDING / METAL-BINDING / TRANSCRIPTION / HELIX-LOOP-HELIX-BETA / DSBH / FACIAL TRIAD / ASPARAGINYL/ASPARTYL HYDROXYLASE / EPIGENETIC REGULATION / SIGNALING / ARD / BETA-HYDROXYLATION / ACTIVATOR-INHIBITOR / OXIDOREDUCTASE-PEPTIDE COMPLEX
Function / homology
Function and homology information


hypoxia-inducible factor-asparagine dioxygenase / : / [protein]-asparagine 3-dioxygenase activity / peptidyl-histidine dioxygenase activity / peptidyl-aspartic acid 3-dioxygenase activity / Cellular response to hypoxia / carboxylic acid binding / positive regulation of vasculogenesis / ankyrin repeat binding / oxygen sensor activity ...hypoxia-inducible factor-asparagine dioxygenase / : / [protein]-asparagine 3-dioxygenase activity / peptidyl-histidine dioxygenase activity / peptidyl-aspartic acid 3-dioxygenase activity / Cellular response to hypoxia / carboxylic acid binding / positive regulation of vasculogenesis / ankyrin repeat binding / oxygen sensor activity / Notch binding / negative regulation of Notch signaling pathway / NF-kappaB binding / positive regulation of myoblast differentiation / ferrous iron binding / transcription corepressor activity / perinuclear region of cytoplasm / protein homodimerization activity / zinc ion binding / nucleoplasm / cytosol / cytoplasm
Similarity search - Function
Clavaminate synthase-like / Hypoxia-inducible factor 1-alpha inhibitor, domain II / Cupin-like domain 8 / Cupin-like domain / A domain family that is part of the cupin metalloenzyme superfamily. / Jelly Rolls / JmjC domain / JmjC domain profile. / RmlC-like jelly roll fold / Helix Hairpins ...Clavaminate synthase-like / Hypoxia-inducible factor 1-alpha inhibitor, domain II / Cupin-like domain 8 / Cupin-like domain / A domain family that is part of the cupin metalloenzyme superfamily. / Jelly Rolls / JmjC domain / JmjC domain profile. / RmlC-like jelly roll fold / Helix Hairpins / Jelly Rolls / Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Chem-A1H / Hypoxia-inducible factor 1-alpha inhibitor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsLeissing, T.M. / Schofield, C.J. / Clifton, I.J. / Lu, X.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Engineering and Physical Sciences Research CouncilG03706X/1 United Kingdom
CitationJournal: Chem Sci / Year: 2017
Title: Molecular and cellular mechanisms of HIF prolyl hydroxylase inhibitors in clinical trials.
Authors: Yeh, T.L. / Leissing, T.M. / Abboud, M.I. / Thinnes, C.C. / Atasoylu, O. / Holt-Martyn, J.P. / Zhang, D. / Tumber, A. / Lippl, K. / Lohans, C.T. / Leung, I.K.H. / Morcrette, H. / Clifton, I. ...Authors: Yeh, T.L. / Leissing, T.M. / Abboud, M.I. / Thinnes, C.C. / Atasoylu, O. / Holt-Martyn, J.P. / Zhang, D. / Tumber, A. / Lippl, K. / Lohans, C.T. / Leung, I.K.H. / Morcrette, H. / Clifton, I.J. / Claridge, T.D.W. / Kawamura, A. / Flashman, E. / Lu, X. / Ratcliffe, P.J. / Chowdhury, R. / Pugh, C.W. / Schofield, C.J.
History
DepositionAug 9, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 18, 2017Provider: repository / Type: Initial release
Revision 1.1Feb 21, 2018Group: Database references / Category: citation / citation_author
Item: _citation.journal_id_ISSN / _citation.journal_volume ..._citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Jan 17, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Hypoxia-inducible factor 1-alpha inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,2678
Polymers40,4151
Non-polymers8527
Water1,11762
1
A: Hypoxia-inducible factor 1-alpha inhibitor
hetero molecules

A: Hypoxia-inducible factor 1-alpha inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)82,53516
Polymers80,8312
Non-polymers1,70414
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_555y,x,-z1
Buried area5070 Å2
ΔGint-95 kcal/mol
Surface area29890 Å2
MethodPISA
Unit cell
Length a, b, c (Å)86.180, 86.180, 148.200
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Hypoxia-inducible factor 1-alpha inhibitor / Factor inhibiting HIF-1 / FIH-1 / Hypoxia-inducible factor asparagine hydroxylase


Mass: 40415.355 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HIF1AN, FIH1 / Production host: Escherichia coli (E. coli)
References: UniProt: Q9NWT6, hypoxia-inducible factor-asparagine dioxygenase, Oxidoreductases; Acting on paired donors, with incorporation or reduction of molecular oxygen; With 2-oxoglutarate as one ...References: UniProt: Q9NWT6, hypoxia-inducible factor-asparagine dioxygenase, Oxidoreductases; Acting on paired donors, with incorporation or reduction of molecular oxygen; With 2-oxoglutarate as one donor, and incorporation of one atom of oxygen into each donor

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Non-polymers , 5 types, 69 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-A1H / 2-(6-morpholin-4-ylpyrimidin-4-yl)-4-(1,2,3-triazol-1-yl)-1~{H}-pyrazol-3-one


Mass: 314.303 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H14N8O2
#4: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 62 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.4 Å3/Da / Density % sol: 63.87 % / Description: Tetragonal bipyramid
Crystal growTemperature: 300 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.1M HEPES pH7.5, 1.4M ammonium sulfate, 4.5% PEG400
Temp details: ambient

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: cryo cooled
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Oct 18, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.3→30.47 Å / Num. obs: 25593 / % possible obs: 99.9 % / Redundancy: 11.3 % / CC1/2: 0.995 / Rmerge(I) obs: 0.148 / Rpim(I) all: 0.046 / Net I/σ(I): 8.9
Reflection shellResolution: 2.3→2.42 Å / Redundancy: 11.5 % / Rmerge(I) obs: 1.229 / Mean I/σ(I) obs: 1.9 / Num. unique obs: 3657 / CC1/2: 0.695 / Rpim(I) all: 0.374 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX(1.10_2155: ???)refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1h2k

1h2k


Resolution: 2.3→30.387 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 25.21 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2142 1240 4.86 %
Rwork0.1992 --
obs0.2 25520 99.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.3→30.387 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2657 0 51 62 2770
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0122807
X-RAY DIFFRACTIONf_angle_d0.6643825
X-RAY DIFFRACTIONf_dihedral_angle_d14.41637
X-RAY DIFFRACTIONf_chiral_restr0.045388
X-RAY DIFFRACTIONf_plane_restr0.004505
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3-2.39210.34661400.29922660X-RAY DIFFRACTION100
2.3921-2.50090.26871120.25192643X-RAY DIFFRACTION100
2.5009-2.63270.2561310.24072648X-RAY DIFFRACTION100
2.6327-2.79750.26791440.22492657X-RAY DIFFRACTION100
2.7975-3.01330.23371370.22752661X-RAY DIFFRACTION100
3.0133-3.31630.26991390.22092683X-RAY DIFFRACTION100
3.3163-3.79530.19731370.18552706X-RAY DIFFRACTION100
3.7953-4.77870.17211570.15452732X-RAY DIFFRACTION100
4.7787-30.38950.20151430.19952890X-RAY DIFFRACTION100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.1676-1.2050.90181.3483-0.58251.6796-0.23720.55410.8352-0.095-0.2875-0.2103-0.32970.40620.45060.4212-0.00880.02720.70380.24070.7714-13.754232.3917-22.6803
22.6903-0.181.70432.55511.20433.29730.0448-0.09650.27670.1371-0.26770.2570.0877-0.51670.2130.3310.01560.03790.55920.10850.476-26.521923.6954-15.483
31.3776-1.7980.29572.8158-0.97510.8877-0.5287-0.41070.37070.91820.1888-0.7629-0.2188-0.15870.37780.6951-0.0277-0.06720.88650.00710.6212-11.973922.95056.8398
43.3807-0.23461.89782.3705-0.01123.301-0.119-1.00730.57330.9027-0.24330.5204-0.1098-1.340.01440.64220.12780.18330.8905-0.00060.4312-30.129729.8295-2.5889
53.5949-1.89181.15125.7732-0.97150.56140.2486-0.4298-0.62780.22330.22750.44630.2957-0.4336-0.56050.4945-0.0564-0.04420.66560.15130.5777-26.557313.3517-16.0213
61.8659-0.37961.36290.99220.27663.24610.1089-0.17240.0450.38790.08410.3240.0536-0.11-0.14440.3550.00550.06020.53280.10560.5013-17.725823.3548-10.0326
72.6798-0.41131.6642.3663-1.03153.36940.04760.02460.28640.14480.01960.13670.00640.088-0.01890.3426-0.0059-0.00170.55110.09630.4689-5.901720.9864-6.5806
85.3738-0.23632.10171.3088-0.10452.02970.01580.03680.24180.1426-0.0449-0.035-0.22670.04110.04020.29220.01870.00550.53330.11060.4419-10.991624.1519-12.4698
92.0206-0.6443-0.46713.3401-0.01260.16110.34150.0795-0.6195-0.2038-0.02340.56530.3454-0.152-0.22520.4572-0.0198-0.12160.44230.0340.6337-6.69352.2147-7.8766
109.0165-0.6311-2.64343.12590.59963.35710.0313-0.1722-0.11330.2229-0.0342-0.2256-0.0525-0.2843-0.2340.5443-0.0241-0.07930.440.06820.33266.11955.41565.7425
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 15 through 49 )
2X-RAY DIFFRACTION2chain 'A' and (resid 50 through 95 )
3X-RAY DIFFRACTION3chain 'A' and (resid 96 through 119 )
4X-RAY DIFFRACTION4chain 'A' and (resid 120 through 166 )
5X-RAY DIFFRACTION5chain 'A' and (resid 167 through 190 )
6X-RAY DIFFRACTION6chain 'A' and (resid 191 through 211 )
7X-RAY DIFFRACTION7chain 'A' and (resid 212 through 246 )
8X-RAY DIFFRACTION8chain 'A' and (resid 247 through 297 )
9X-RAY DIFFRACTION9chain 'A' and (resid 298 through 329 )
10X-RAY DIFFRACTION10chain 'A' and (resid 330 through 349 )

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